Use of a botulinum neurotoxin to alleviate various disorders

ABSTRACT

Methods for treating obsessions and compulsions by local administration of a Clostridial toxin. The obsessions or compulsions can be eye poking, body rocking, finger biting, counting, checking and related disorders treated by low dose, intramuscular administration of a botulinum toxin.

CROSS-REFERENCE

This application is a continuation of prior application Ser. No.10/423,380, filed Apr. 25, 2003, now U.S. Pat. No. 7,393,537, thecontents of which are hereby incorporated by reference in theirentirety.

BACKGROUND

The present invention relates to methods for treating certain obsessivecompulsive disorders. In particular, the present invention includesmethods for treating various repetitive and/or injurious motor activitysymptoms of certain obsessive compulsive disorders by peripheraladministration of a Clostridial toxin.

Obsessions are persistent ideas, thoughts, impulses or mental imagesthat cause distress and anxiety. Obsessions can involve themes ofaggression, contamination, sex or somatic concerns. Compulsions arerepetitive, stereotyped motor acts an individual feels required toperform to reduce anxiety or distress. The compulsion usually can beresisted only temporarily, with resistance followed by an increasingsense of unease and tension. The mounting tension is released only byperforming the irrational motor act or ritual. Compulsions very incomplexity from simple actions such as touching, lip licking, tappingand rubbing to complex behaviors such as repetitive hand washing, hairpulling and body rocking. Additionally, compulsive behaviors can includehoarding, repeating, checking (i.e. repeated checking that a door islocked), counting (i.e. compulsive counting of footsteps) and arrangingbehaviors, as well as various self-injurious behaviors, such asself-biting (i.e. finger biting), head banging, eye poking, skinpicking, skin cutting, skin burning, eye enucleation and castration.Unfortunates with such disturbing self-injurious compulsions mustfrequently be restrained or fitted with suitable restraints (such as amouth guard) to prevent further injury to themselves. These compulsionscan be severely disabling and can accompany psychosis, intoxication,Tourette's syndrome and mental retardation.

Thus, obsessive compulsive disorders can combine both obsessive thoughtsand compulsive behaviors, and can be defined as a chronic conditioncharacterized by recurrent intrusive thoughts and ritualistic behaviorsthat consume much of the afflicted person's attention and activity,thereby impairing everyday functioning. The behaviors of an obsessiveand/or compulsive disorder typically begin in late childhood or earlyadulthood and the patient experiences marked tension and distress uponresisting the obsessions and compulsions. Epidemiologic data indicates alifetime prevalence of 2 to 3 percent worldwide and obsessive compulsivedisorders are more common in males and in first born children. See e.g.page 2490 of Fauci, A. S. et al., editors, Harrison's Principles ofInternal Medicine, McGraw Hill, fourteenth edition (1998).

Functional neuroimaging (i.e. positron emission tomography) studies,brain lesion analysis, and the results of neurosurgical intervention totreat obsessive compulsive disorders indicate that dysfunction withinparticular basal ganglia and ventral prefrontal cortical structuresprovides a proposed pathophysiology for obsessive compulsive disorders.See e.g. pages 963-964 of Zigmond, M. J. et al, editors, FundamentalNeuroscience, Academic Press (1999).

Clearly, obsessive compulsive disorders can cause great embarrassment,distress and anguish to both the cognizant patient so afflicted as wellas to his or her caregiver.

Tourette's Syndrome

Tourette's syndrome is usually characterized by multiple motor tics andone or more vocal tics. The tics can appear simultaneously or atdifferent periods during the illness. The tics can occur many times aday, and recurrently throughout a period of more than one year. Duringthis period, there is almost never a tic-free period of more than a fewconsecutive months. Those afflicted with Tourette's syndrome sufferdisturbances which can comprise complex tics and cause marked distressor significant impairment in social, occupational, and other importantareas of functioning. The onset of the disorder is typically before theage of eighteen. The complex tics of Tourette's syndrome are not due tothe direct physiological effects of a substance (e.g., stimulants) or ageneral medical condition (e.g., Huntington's disease or postviralencephalitis) and are thought to be a part of the Tourette's diseaseprocess. The anatomical location, number, frequency, complexity, andseverity of the tics often change over time. The tics typically involvethe head and, frequently, other parts of the body, such as the torso andupper and lower limbs. The vocal tics include various words or soundssuch as clicks, grunts, yelps, barks, sniffs, snorts, and coughs.Coprolalia (a complex vocal tic involving the uttering of obscenities),is present in a few individuals (less than 10%) with this disorder.Complex motor tics involving touching, squatting, deep knee bends,retracing steps, and twirling when walking may be present. Inapproximately one-half the individuals with this disorder. The firstsymptoms to appear are often bouts of a single tic, most frequently eyeblinking, less frequently tics involving another part of the face or thebody. Initial symptoms can also include tongue protrusion, squatting,sniffing, hopping, skipping, throat clearing, stuttering, utteringsounds or words, and coprolalia.

Whereas the repetitive motor activities symptomatic of Tourette'ssyndrome can be characterized as true tics (that is, as habitual,repeated contraction of certain muscles, as in throat clearing,sniffing, lip pursing or excessive blinking) they are an isolated anddistinct subset of behaviors distinct from obsessive compulsivedisorders, as defined by the Diagnostic and Statistical Manual of theAmerican Psychiatric Association (the “DSM-IVR”, fourth revisededition). There are a number of obsessive and/or compulsive disorderswhich involve more complex non tic repetitive motor activity, frequentlyinjurious, as can occur in dermatillomania, trichotillomania, handwashing, head banging, eye poking, body rocking, finger biting,counting, and checking disorders.

Dermatillomania (Compulsive Skin Picking)

The primary characteristic of compulsive skin picking is the repetitivepicking at one's own skin to the extent of causing damage. Usually, butnot always, the face is the primary location for skin picking. Howevercompulsive skin picking, also known as dermatillomania or neuroticexcoriation, can involve any part of the body. Individuals withcompulsive skin picking may pick at normal skin variations such asfreckles and moles, at actual pre-existing scabs, sores or acneblemishes, or at imagined skin defects that nobody else can observe. Thecompulsive skin picking patient may use his or her fingernails, as wellas their teeth, tweezers, pins or other mechanical devices. As a result,dermatillomania can cause bleeding, bruises, infections, and/orpermanent disfigurement of the skin.

Sometimes skin-picking is preceded by a high level of tension and astrong itch or urge to pick. Likewise, carrying out the skin-picking canbe followed by a feeling of relief or pleasure. A compulsive skinpicking episode can be a conscious response to anxiety or depression,but is frequently done as an unconscious habit. Individuals withcompulsive skin picking often attempt to camouflage the damage caused totheir skin by using make-up or wearing clothes to cover the subsequentmarks and scars. In extreme cases, individuals with compulsive skinpicking avoid social situations in an effort to prevent others fromseeing the scars, scabs, and bruises that result from skin picking.

The primary treatment modality for compulsive skin picking depends onthe level of awareness the individual has regarding the problem. If thecompulsive skin picking is generally an unconscious habit, the primarytreatment is a form of cognitive-behavioral therapy called habitreversal training (HRT). HRT is based on the principle that skin-pickingis a conditioned response to specific situations and events, and thatthe individual with compulsive skin picking is frequently unaware ofthese triggers. HRT challenges the problem in a two-fold process. First,the individual with compulsive skin picking learns how to become moreconsciously aware of situations and events that trigger skin-pickingepisodes. Second, the individual learns to utilize alternative behaviorsin response to these situations and events. Unfortunately HRT does nothave a high success rate. If the patient is unaware of or not fullycognizant of his compulsive skin picking, pharmacologic therapy isrecommended. Significant side effects have occurred from the currentdrug therapy.

Trichotillomania (Compulsive Hair Pulling)

Trichotillomania (TTM) is an compulsive disorder where the patient pullsout his or her hair from the scalp, eyelashes, eyebrows, or other partsof the body, resulting in noticeable bald patches. Thus symptoms oftrichotillomania includes recurrent pulling out of one's hair resultingin noticeable hair loss, and this is usually preceded by an increasingsense of tension immediately before pulling out the hair or whenresisting the behavior, followed by pleasure, gratification, or reliefwhile the hair is being pulled out. This disorder can cause significantdistress and impairment in social, occupational, or other importantareas of functioning. It is estimated that trichotillomania affects oneto two percent of the population, or four to eleven million Americans.TTM seems to strike most frequently in the pre- or early adolescentyears. The typical first-time hair puller is 12 years old, although TTMhas affected people as young as one and as old as seventy. About ninetypercent of those with TTM are women.

Although the symptoms range greatly in severity, location on the body,and response to treatment, most people with TTM pull enough hair over along enough period of time that they have bald spots on their heads (ormissing eyelashes, eyebrows, pubic, or underarm hair), which they go togreat lengths to cover with hairstyles, scarves or clothing, or makeup.The persistence of the compulsion can vary considerably, at times, theurge may be so strong that it makes thinking of anything else nearlyimpossible.

Treatments for TTM include behavioral therapy and drugs. In behavioraltherapy, patients learn a structured method of keeping track of thesymptoms and associated behaviors, increasing awareness of pulling,substituting incompatible behaviors and several other techniques aimedat reversing the “habit” of pulling. Although medications clearly helpsome people temporarily, symptoms are likely to return when themedication is stopped unless behavioral therapy is incorporated intotreatment. Medications may help to reduce the depression and anyobsessive-compulsive symptoms the person may be experiencing. Commonlyused medications include fluoxetine (PROZAC), fluvoxamine (LUVOX),sertraline (ZOLOFT), paroxetine (PAXIL), clomipramine (ANAFRANIL),valproate (DEPAKOTE), and lithium carbonate (LITHOBID, ESKALITH).Unfortunately, behavioral therapies have limited success, and the drugstherapies can have significant side effects and require regular, chronicrepeat dosings.

Thus, there are many drawbacks and deficiencies with current obsessivecompulsive disorder therapies. Treatment regimes available includechronic administration of drugs which inhibit serotonin reuptake (suchdrugs are called SSRIs or serotonin reuptake inhibitors) and behaviormodification therapies. Clomipramine, fluoxetine and fluvoxamine areapproved for the treatment of obsessive compulsive disorders. Notably,clomipramine is a tricyclic antidepressant which is poorly tolerated dueto significant anticholinergic and sedative side effects. Additionally,fluoxetine and fluvoxamine (SSRIs) also have a side effect profile,which can include cardiac arrhythmias, although they tend to be morebenign that clomipramine. Furthermore, only about 50 to 60 percent ofpatients with an obsessive compulsive disorder show an acceptable degreeof improvement when either or both pharmacotherapies, and behaviormodification strategies have been tried.

Botulinum Toxin

The genus Clostridium has more than one hundred and twenty sevenspecies, grouped according to their morphology and functions. Theanaerobic, gram positive bacterium Clostridium botulinum produces apotent polypeptide neurotoxin, botulinum toxin, which causes aneuroparalytic illness in humans and animals referred to as botulism.The spores of Clostridium botulinum are found in soil and can grow inimproperly sterilized and sealed food containers of home basedcanneries, which are the cause of many of the cases of botulism. Theeffects of botulism typically appear 18 to 36 hours after eating thefoodstuffs infected with a Clostridium botulinum culture or spores. Thebotulinum toxin can apparently pass unattenuated through the lining ofthe gut and attack peripheral motor neurons. Symptoms of botulinum toxinintoxication can progress from difficulty walking, swallowing, andspeaking to paralysis of the respiratory muscles and death.

Botulinum toxin type A is the most lethal natural biological agent knownto man. About 50 picograms of a commercially available botulinum toxintype A (purified neurotoxin complex)¹ is a LD₅₀ in mice (i.e. 1 unit).One unit of BOTOX® contains about 50 picograms (about 56 attomoles) ofbotulinum toxin type A complex. Interestingly, on a molar basis,botulinum toxin type A is about 1.8 billion times more lethal thandiphtheria, about 600 million times more lethal than sodium cyanide,about 30 million times more lethal than cobra toxin and about 12 milliontimes more lethal than cholera. Singh, Critical Aspects of BacterialProtein Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited byB. R. Singh et al., Plenum Press, New York (1976) (where the stated LD₅₀of botulinum toxin type A of 0.3 ng equals 1 U is corrected for the factthat about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of botulinumtoxin is defined as the LD₅₀ upon intraperitoneal injection into femaleSwiss Webster mice weighing 18 to 20 grams each. ¹ Available fromAllergan, Inc., of Irvine, Calif. under the tradename BOTOX® in 100 unitvials)

Seven generally immunologically distinct botulinum neurotoxins have beencharacterized, these being respectively botulinum neurotoxin serotypesA, B, C₁, D, E, F and G each of which is distinguished by neutralizationwith type-specific antibodies. The different serotypes of botulinumtoxin vary in the animal species that they affect and in the severityand duration of the paralysis they evoke. For example, it has beendetermined that botulinum toxin type A is 500 times more potent, asmeasured by the rate of paralysis produced in the rat, than is botulinumtoxin type B. Additionally, botulinum toxin type B has been determinedto be non-toxic in primates at a dose of 480 U/kg which is about 12times the primate LD₅₀ for botulinum toxin type A. Moyer E et al.,Botulinum Toxin Type B: Experimental and Clinical Experience, beingchapter 6, pages 71-85 of “Therapy With Botulinum Toxin”, edited byJankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxinapparently binds with high affinity to cholinergic motor neurons, istranslocated into the neuron and blocks the release of acetylcholine.Additional uptake can take place through low affinity receptors, as wellas by phagocytosis and pinocytosis.

Regardless of serotype, the molecular mechanism of toxin intoxicationappears to be similar and to involve at least three steps or stages. Inthe first step of the process, the toxin binds to the presynapticmembrane of the target neuron through a specific interaction between theheavy chain, H chain, and a cell surface receptor; the receptor isthought to be different for each type of botulinum toxin and for tetanustoxin. The carboxyl end segment of the H chain, H_(C), appears to beimportant for targeting of the toxin to the cell surface.

In the second step, the toxin crosses the plasma membrane of thepoisoned cell. The toxin is first engulfed by the cell throughreceptor-mediated endocytosis, and an endosome containing the toxin isformed. The toxin then escapes the endosome into the cytoplasm of thecell. This step is thought to be mediated by the amino end segment ofthe H chain, H_(N), which triggers a conformational change of the toxinin response to a pH of about 5.5 or lower. Endosomes are known topossess a proton pump which decreases intra-endosomal pH. Theconformational shift exposes hydrophobic residues in the toxin, whichpermits the toxin to embed itself in the endosomal membrane. The toxin(or at a minimum the light chain) then translocates through theendosomal membrane into the cytoplasm.

The last step of the mechanism of botulinum toxin activity appears toinvolve reduction of the disulfide bond joining the heavy chain, Hchain, and the light chain, L chain. The entire toxic activity ofbotulinum and tetanus toxins is contained in the L chain of theholotoxin; the L chain is a zinc (Zn++) endopeptidase which selectivelycleaves proteins essential for recognition and docking ofneurotransmitter-containing vesicles with the cytoplasmic surface of theplasma membrane, and fusion of the vesicles with the plasma membrane.Tetanus neurotoxin, botulinum toxin types B, D, F, and G causedegradation of synaptobrevin (also called vesicle-associated membraneprotein (VAMP)), a synaptosomal membrane protein. Most of the VAMPpresent at the cytoplasmic surface of the synaptic vesicle is removed asa result of any one of these cleavage events. Botulinum toxin serotype Aand E cleave SNAP-25. Botulinum toxin serotype C₁ was originally thoughtto cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Eachof the botulinum toxins specifically cleaves a different bond, exceptbotulinum toxin type B (and tetanus toxin) which cleave the same bond.Each of these cleavages block the process of vesicle-membrane docking,thereby preventing exocytosis of vesicle content.

Botulinum toxins have been used in clinical settings for the treatmentof neuromuscular disorders characterized by hyperactive skeletal muscles(i.e. motor disorders). In 1989 a botulinum toxin type A complex hasbeen approved by the U.S. Food and Drug Administration for the treatmentof blepharospasm, strabismus and hemifacial spasm. Subsequently, abotulinum toxin type A was also approved by the FDA for the treatment ofcervical dystonia and for the treatment of glabellar lines, and abotulinum toxin type B was approved for the treatment of cervicaldystonia. Non-type A botulinum toxin serotypes apparently have a lowerpotency and/or a shorter duration of activity as compared to botulinumtoxin type A. Clinical effects of peripheral intramuscular botulinumtoxin type A are usually seen within one week of injection. The typicalduration of symptomatic relief from a single intramuscular injection ofbotulinum toxin type A averages about three months, althoughsignificantly longer periods of therapeutic activity have been reported.

Although all the botulinum toxins serotypes apparently inhibit releaseof the neurotransmitter acetylcholine at the neuromuscular junction,they do so by affecting different neurosecretory proteins and/orcleaving these proteins at different sites. For example, botulinum typesA and E both cleave the 25 kiloDalton (kD) synaptosomal associatedprotein (SNAP-25), but they target different amino acid sequences withinthis protein. Botulinum toxin types B, D, F and G act onvesicle-associated protein (VAMP, also called synaptobrevin), with eachserotype cleaving the protein at a different site. Finally, botulinumtoxin type C₁ has been shown to cleave both syntaxin and SNAP-25. Thesedifferences in mechanism of action may affect the relative potencyand/or duration of action of the various botulinum toxin serotypes.Apparently, a substrate for a botulinum toxin can be found in a varietyof different cell types. See e.g. Biochem J 1; 339 (pt 1):159-65:1999,and Mov Disord, 10(3):376:1995 (pancreatic islet B cells contains atleast SNAP-25 and synaptobrevin).

The molecular weight of the botulinum toxin protein molecule, for allseven of the known botulinum toxin serotypes, is about 150 kD.Interestingly, the botulinum toxins are released by Clostridialbacterium as complexes comprising the 150 kD botulinum toxin proteinmolecule along with associated non-toxin proteins. Thus, the botulinumtoxin type A complex can be produced by Clostridial bacterium as 900 kD,500 kD and 300 kD forms. Botulinum toxin types B and C₁ is apparentlyproduced as only a 700 kD or 500 kD complex. Botulinum toxin type D isproduced as both 300 kD and 500 kD complexes. Finally, botulinum toxintypes E and F are produced as only approximately 300 kD complexes. Thecomplexes (i.e. molecular weight greater than about 150 kD) are believedto contain a non-toxin hemaglutinin protein and a non-toxin andnon-toxic nonhemaglutinin protein. These two non-toxin proteins (whichalong with the botulinum toxin molecule comprise the relevant neurotoxincomplex) may act to provide stability against denaturation to thebotulinum toxin molecule and protection against digestive acids whentoxin is ingested. Additionally, it is possible that the larger (greaterthan about 150 kD molecular weight) botulinum toxin complexes may resultin a slower rate of diffusion of the botulinum toxin away from a site ofintramuscular injection of a botulinum toxin complex.

In vitro studies have indicated that botulinum toxin inhibits potassiumcation induced release of both acetylcholine and norepinephrine fromprimary cell cultures of brainstem tissue. Additionally, it has beenreported that botulinum toxin inhibits the evoked release of bothglycine and glutamate in primary cultures of spinal cord neurons andthat in brain synaptosome preparations botulinum toxin inhibits therelease of each of the neurotransmitters acetylcholine, dopamine,norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A andC Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain, JNeurochem 51(2); 522-527:1988) CGRP, substance P and glutamate(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks GlutamateExocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.Biochem 165; 675-681:1897. Thus, when adequate concentrations are used,stimulus-evoked release of most neurotransmitters is blocked bybotulinum toxin. See e.g. Pearce, L. B., Pharmacologic Characterizationof Botulinum Toxin For Basic Science and Medicine, Toxicon 35(9);1373-1412 at 1393; Bigalke H., et al., Botulinum A Neurotoxin InhibitsNon-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons inCulture, Brain Research 360; 318-324:1985; Habermann E., Inhibition byTetanus and Botulinum A Toxin of the release of [ ³ H]Noradrenaline and[ ³ H]GABA From Rat Brain Homogenate, Experientia 44; 224-226:1988,Bigalke H., et al., Tetanus Toxin and Botulinum A Toxin Inhibit Releaseand Uptake of Various Transmitters, as Studied with ParticulatePreparations From Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's ArchPharmacol 316; 244-251:1981, and; Jankovic J. et al., Therapy WithBotulinum Toxin, Marcel Dekker, Inc., (1994), page 5.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures. Allthe botulinum toxin serotypes are initially synthesized as inactivesingle chain proteins which must be cleaved or nicked by proteases tobecome neuroactive. The bacterial strains that make botulinum toxinserotypes A and G possess endogenous proteases and serotypes A and G cantherefore be recovered from bacterial cultures in predominantly theiractive form. In contrast, botulinum toxin serotypes C₁, D and E aresynthesized by nonproteolytic strains and are therefore typicallyunactivated when recovered from culture. Serotypes B and F are producedby both proteolytic and nonproteolytic strains and therefore can berecovered in either the active or inactive form. However, even theproteolytic strains that produce, for example, the botulinum toxin typeB serotype only cleave a portion of the toxin produced. The exactproportion of nicked to unnicked molecules depends on the length ofincubation and the temperature of the culture. Therefore, a certainpercentage of any preparation of, for example, the botulinum toxin typeB toxin is likely to be inactive, possibly accounting for the knownsignificantly lower potency of botulinum toxin type B as compared tobotulinum toxin type A. The presence of inactive botulinum toxinmolecules in a clinical preparation will contribute to the overallprotein load of the preparation, which has been linked to increasedantigenicity, without contributing to its clinical efficacy.Additionally, it is known that botulinum toxin type B has, uponintramuscular injection, a shorter duration of activity and is also lesspotent than botulinum toxin type A at the same dose level.

High quality crystalline botulinum toxin type A can be produced from theHall A strain of Clostridium botulinum with characteristics of ≧3×10⁷U/mg, an A₂₆₀/A₂₇₈ of less than 0.60 and a distinct pattern of bandingon gel electrophoresis. The known Schantz process can be used to obtaincrystalline botulinum toxin type A, as set forth in Schantz, E. J., etal, Properties and use of Botulinum toxin and Other MicrobialNeurotoxins in Medicine, Microbiol Rev. 56; 80-99:1992. Generally, thebotulinum toxin type A complex can be isolated and purified from ananaerobic fermentation by cultivating Clostridium botulinum type A in asuitable medium. The known process can also be used, upon separation outof the non-toxin proteins, to obtain pure botulinum toxins, such as forexample: purified botulinum toxin type A with an approximately 150 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater; purified botulinum toxin type B with an approximately 156 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater, and; purified botulinum toxin type F with an approximately 155kD molecular weight with a specific potency of 1-2×10⁷ LD₅₀ U/mg orgreater.

Botulinum toxins and/or botulinum toxin complexes can be obtained fromList Biological Laboratories, Inc., Campbell, Calif.; the Centre forApplied Microbiology and Research, Porton Down, U.K.; Wako (Osaka,Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals ofSt Louis, Mo. Pure botulinum toxin can also be used to prepare apharmaceutical composition.

As with enzymes generally, the biological activities of the botulinumtoxins (which are intracellular peptidases) is dependant, at least inpart, upon their three dimensional conformation. Thus, botulinum toxintype A is detoxified by heat, various chemicals surface stretching andsurface drying. Additionally, it is known that dilution of the toxincomplex obtained by the known culturing, fermentation and purificationto the much, much lower toxin concentrations used for pharmaceuticalcomposition formulation results in rapid detoxification of the toxinunless a suitable stabilizing agent is present. Dilution of the toxinfrom milligram quantities to a solution containing nanograms permilliliter presents significant difficulties because of the rapid lossof specific toxicity upon such great dilution. Since the toxin may beused months or years after the toxin containing pharmaceuticalcomposition is formulated, the toxin can stabilized with a stabilizingagent such as albumin and gelatin.

A commercially available botulinum toxin containing pharmaceuticalcomposition is sold under the trademark BOTOX® (available from Allergan,Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxintype A complex, albumin and sodium chloride packaged in sterile,vacuum-dried form. The botulinum toxin type A is made from a culture ofthe Hall strain of Clostridium botulinum grown in a medium containingN-Z amine and yeast extract. The botulinum toxin type A complex ispurified from the culture solution by a series of acid precipitations toa crystalline complex consisting of the active high molecular weighttoxin protein and an associated hemagglutinin protein. The crystallinecomplex is re-dissolved in a solution containing saline and albumin andsterile filtered (0.2 microns) prior to vacuum-drying. The vacuum-driedproduct is stored in a freezer at or below −5° C. BOTOX® can bereconstituted with sterile, non-preserved saline prior to intramuscularinjection. Each vial of BOTOX® contains about 100 units (U) ofClostridium botulinum toxin type A purified neurotoxin complex, 0.5milligrams of human serum albumin and 0.9 milligrams of sodium chloridein a sterile, vacuum-dried form without a preservative.

To reconstitute vacuum-dried BOTOX®, sterile normal saline without apreservative; (0.9% Sodium Chloride Injection) is used by drawing up theproper amount of diluent in the appropriate size syringe. Since BOTOX®may be denatured by bubbling or similar violent agitation, the diluentis gently injected into the vial. For sterility reasons BOTOX® ispreferably administered within four hours after the vial is removed fromthe freezer and reconstituted. During these four hours, reconstitutedBOTOX® can be stored in a refrigerator at about 2° C. to about 8° C.Reconstituted, refrigerated BOTOX® has been reported to retain itspotency for at least about two weeks. Neurology, 48:249-53:1997.

It has been reported that botulinum toxin type A has been used inclinical settings as follows:

(1) about 75-125 units of BOTOX® per intramuscular injection (multiplemuscles) to treat cervical dystonia;

(2) 5-10 units of BOTOX® per intramuscular injection to treat glabellarlines (brow furrows) (5 units injected intramuscularly into the procerusmuscle and 10 units injected intramuscularly into each corrugatorsupercilii muscle);

(3) about 30-80 units of BOTOX® to treat constipation by intrasphincterinjection of the puborectalis muscle;

(4) about 1-5 units per muscle of intramuscularly injected BOTOX® totreat blepharospasm by injecting the lateral pre-tarsal orbicularisoculi muscle of the upper lid and the lateral pre-tarsal orbicularisoculi of the lower lid.

(5) to treat strabismus, extraocular muscles have been injectedintramuscularly with between about 1-5 units of BOTOX®, the amountinjected varying based upon both the size of the muscle to be injectedand the extent of muscle paralysis desired (i.e. amount of dioptercorrection desired).(6) to treat upper limb spasticity following stroke by intramuscularinjections of BOTOX® into five different upper limb flexor muscles, asfollows:(a) flexor digitorum profundus: 7.5 U to 30 U(b) flexor digitorum sublimus: 7.5 U to 30 U(c) flexor carpi ulnaris: 10 U to 40 U(d) flexor carpi radialis: 15 U to 60 U(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscleshas been injected at the same treatment session, so that the patientreceives from 90 U to 360 U of upper limb flexor muscle BOTOX® byintramuscular injection at each treatment session.(7) to treat migraine, pericranial injected (injected symmetrically intoglabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX®has showed significant benefit as a prophylactic treatment of migrainecompared to vehicle as measured by decreased measures of migrainefrequency, maximal severity, associated vomiting and acute medicationuse over the three month period following the 25 U injection.

Additionally, intramuscular botulinum toxin has been used in thetreatment of tremor in patients with Parkinson's disease, although ithas been reported that results have not been impressive. Marjama-Lyons,J., et al., Tremor-Predominant Parkinson's Disease, Drugs & Aging 16(4);273-278:2000.

It is known that botulinum toxin type A can have an efficacy for up to12 months (European J. Neurology 6 (Supp 4): S111-S1150:1999), and insome circumstances for as long as 27 months. The Laryngoscope109:1344-1346:1999. However, the usual duration of an intramuscularinjection of Botox® is typically about 3 to 4 months.

The success of botulinum toxin type A to treat a variety of clinicalconditions has led to interest in other botulinum toxin serotypes. Twocommercially available botulinum type A preparations for use in humansare BOTOX® available from Allergan, Inc., of Irvine, Calif., andDYSPORT® available from Beaufour Ipsen, Porton Down, England. ABotulinum toxin type B preparation (MYOBLOC®) is available from ElanPharmaceuticals of San Francisco, Calif.

In addition to having pharmacologic actions at the peripheral location,botulinum toxins may also have inhibitory effects in the central nervoussystem. Work by Weigand et al, Naunyn-Schmiedeberg's Arch. Pharmacol.1976; 292, 161-165, and Habermann, Naunyn-Schmiedeberg's Arch.Pharmacol. 1974; 281, 47-56 showed that botulinum toxin is able toascend to the spinal area by retrograde transport. As such, a botulinumtoxin injected at a peripheral location, for example intramuscularly,may be retrograde transported to the spinal cord.

U.S. Pat. No. 5,989,545 discloses that a modified clostridial neurotoxinor fragment thereof, preferably a botulinum toxin, chemically conjugatedor recombinantly fused to a particular targeting moiety can be used totreat pain by administration of the agent to the spinal cord.

A botulinum toxin has also been proposed for the treatment ofrhinorrhea, hyperhydrosis and other disorders mediated by the autonomicnervous system (U.S. Pat. No. 5,766,605), tension headache, (U.S. Pat.No. 6,458,365), migraine headache (U.S. Pat. No. 5,714,468),post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), paintreatment by intraspinal toxin administration (U.S. Pat. No. 6,113,915),Parkinson's disease and other diseases with a motor disorder component,by intracranial toxin administration (U.S. Pat. No. 6,306,403), hairgrowth and hair retention (U.S. Pat. No. 6,299,893), psoriasis anddermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. No.6,423,319, various cancers (U.S. Pat. No. 6,139,845), pancreaticdisorders (U.S. Pat. No. 6,143,306), smooth muscle disorders (U.S. Pat.No. 5,437,291, including injection of a botulinum toxin into the upperand lower esophageal, pyloric and anal sphincters)), prostate disorders(U.S. Pat. No. 6,365,164), inflammation, arthritis and gout (U.S. Pat.No. 6,063,768), juvenile cerebral palsy (U.S. Pat. No. 6,395,277), innerear disorders (U.S. Pat. No. 6,265,379), thyroid disorders (U.S. Pat.No. 6,358,513), parathyroid disorders (U.S. Pat. No. 6,328,977).Additionally, controlled release toxin implants are known (see e.g. U.S.Pat. Nos. 6,306,423 and 6,312,708).

A botulinum toxin has been used to treat recalcitrant restless legsyndrome (Kudelko, K. M., et al., Successful treatment of recalcitrantRestless Legs Syndrome with botulinum toxin A, Mov Disord 2002; 17(Suppl 5):S242). Restless leg syndrome (RLS) involves an uncomfortablesensation in muscles, usually in the legs and thighs that occurs mostcommonly in middle aged woman. The abnormal sensation is relieved bymoving the legs. RLS is not an obsessive compulsive disorder because itis not characterized by either recurrent intrusive thoughts orritualistic behaviors. The amount of a botulinum toxin administered totreat restless leg syndrome (i.e. 25-50 units of a type A botulinumtoxin per leg) exceeds the amount of toxin typically used to reduce thetone of a hypertonic or rigid thigh muscle, and can indeed can causesome paralysis of the injected thigh muscle.

Additionally, the finger biting, lip biting and tongue biting selfmutilation behaviors of Lesch Nyhan syndrome have been treated byinjecting a botulinum toxin into the chewing or clenching muscles of themouth in one patient. Dabrowski E., et al, Botulinum toxin as a noveltreatment for self-mutilation in Lesch-Nyhan syndrome, Ann Neurol 2002September; 52 (3 Supp 1): S157. Injection of the fingers, lips or tongueis believed contraindicated because of the ulceration and sensitivity ofthese extremities due to the injurious behaviors of the syndrome.

Furthermore, a botulinum toxin has been used to treat focal dystonictics or muscle spasms of Tourette's syndrome. Jankovic, J., Botulinumtoxin in the treatment of tics associated with Tourette's syndrome,Neurology 1993 April; 43 (4 Supp 2): A310; Jankovic, J., Botulinum toxinin the treatment of dystonic tics, Mov Disord 1994 May; 9(3): 347-9,and; Krauss J., et al., Severe motor tics causing cervical myelopathy inTourette's syndrome, Mov Disord 1996; 11 (5): 563-6. These publicationsindicate that a botulinum toxin can act to treat a Tourette's syndrometic both by reducing the force of contraction necessary to generate themuscle movement (i.e. by a partial paralysis of the tic involvedmuscles) as well as by an inhibition or resolution of the premonitorysymptoms (i.e. by removing the urge to carry out or to accomplish thetic) which precede the tic. Unfortunately, significant neck pain, neckweakness and neck pain was reported in some of the Tourette's syndromepatient's administered a botulinum toxin to treat a neck tic.Additionally, the literature is contradictory with regard to use of abotulinum toxin to treat a Tourette's syndrome tic, as others havereported no relief upon use of botulinum toxin to treat a Tourettesyndrome tic, even at dose levels that caused muscle weakness orparalysis. Chappell, P. B., et al., Future therapies of Tourettesyndrome, Neurol Clin 1997 May; 15(2): 429-50, at 444.

Tetanus toxin, as well as derivatives (i.e. with a non-native targetingmoiety), fragments, hybrids and chimeras thereof can also havetherapeutic utility. The tetanus toxin bears many similarities to thebotulinum toxins. Thus, both the tetanus toxin and the botulinum toxinsare polypeptides made by closely related species of Clostridium(Clostridium tetani and Clostridium botulinum, respectively).Additionally, both the tetanus toxin and the botulinum toxins aredichain proteins composed of a light chain (molecular weight about 50kD) covalently bound by a single disulfide bond to a heavy chain(molecular weight about 100 kD). Hence, the molecular weight of tetanustoxin and of each of the seven botulinum toxins (non-complexed) is about150 kD. Furthermore, for both the tetanus toxin and the botulinumtoxins, the light chain bears the domain which exhibits intracellularbiological (protease) activity, while the heavy chain comprises thereceptor binding (immunogenic) and cell membrane translocationaldomains.

Further, both the tetanus toxin and the botulinum toxins exhibit a high,specific affinity for gangliocide receptors on the surface ofpresynaptic cholinergic neurons. Receptor mediated endocytosis oftetanus toxin by peripheral cholinergic neurons results in retrogradeaxonal transport, blocking of the release of inhibitoryneurotransmitters from central synapses and a spastic paralysis.Contrarily, receptor mediated endocytosis of botulinum toxin byperipheral cholinergic neurons results in little if any retrogradetransport, inhibition of acetylcholine exocytosis from the intoxicatedperipheral motor neurons and a flaccid paralysis.

Finally, the tetanus toxin and the botulinum toxins resemble each otherin both biosynthesis and molecular architecture. Thus, there is anoverall 34% identity between the protein sequences of tetanus toxin andbotulinum toxin type A, and a sequence identity as high as 62% for somefunctional domains. Binz T. et al., The Complete Sequence of BotulinumNeurotoxin Type A and Comparison with Other Clostridial Neurotoxins, JBiological Chemistry 265(16); 9153-9158:1990.

Acetylcholine

Typically only a single type of small molecule neurotransmitter isreleased by each type of neuron in the mammalian nervous system,although there is evidence which suggests that several neuromodulatorscan be released by the same neuron. The neurotransmitter acetylcholineis secreted by neurons in many areas of the brain, but specifically bythe large pyramidal cells of the motor cortex, by several differentneurons in the basal ganglia, by the motor neurons that innervate theskeletal muscles, by the preganglionic neurons of the autonomic nervoussystem (both sympathetic and parasympathetic), by the bag 1 fibers ofthe muscle spindle fiber, by the postganglionic neurons of theparasympathetic nervous system, and by some of the postganglionicneurons of the sympathetic nervous system. Essentially, only thepostganglionic sympathetic nerve fibers to the sweat glands, thepiloerector muscles and a few blood vessels are cholinergic as most ofthe postganglionic neurons of the sympathetic nervous system secret theneurotransmitter norepinephine. In most instances acetylcholine has anexcitatory effect. However, acetylcholine is known to have inhibitoryeffects at some of the peripheral parasympathetic nerve endings, such asinhibition of heart rate by the vagal nerve.

The efferent signals of the autonomic nervous system are transmitted tothe body through either the sympathetic nervous system or theparasympathetic nervous system. The preganglionic neurons of thesympathetic nervous system extend from preganglionic sympathetic neuroncell bodies located in the intermediolateral horn of the spinal cord.The preganglionic sympathetic nerve fibers, extending from the cellbody, synapse with postganglionic neurons located in either aparavertebral sympathetic ganglion or in a prevertebral ganglion. Since,the preganglionic neurons of both the sympathetic and parasympatheticnervous system are cholinergic, application of acetylcholine to theganglia will excite both sympathetic and parasympathetic postganglionicneurons.

Acetylcholine activates two types of receptors, muscarinic and nicotinicreceptors. The muscarinic receptors are found in all effector cellsstimulated by the postganglionic, neurons of the parasympathetic nervoussystem as well as in those stimulated by the postganglionic cholinergicneurons of the sympathetic nervous system. The nicotinic receptors arefound in the adrenal medulla, as well as within the autonomic ganglia,that is on the cell surface of the postganglionic neuron at the synapsebetween the preganglionic and postganglionic neurons of both thesympathetic and parasympathetic systems. Nicotinic receptors are alsofound in many nonautonomic nerve endings, for example in the membranesof skeletal muscle fibers at the neuromuscular junction.

Acetylcholine is released from cholinergic neurons when small, clear,intracellular vesicles fuse with the presynaptic neuronal cell membrane.A wide variety of non-neuronal secretory cells, such as, adrenal medulla(as well as the PC12 cell line) and pancreatic islet cells releasecatecholamines and parathyroid hormone, respectively, from largedense-core vesicles. The PC 2 cell line is a clone of ratpheochromocytoma cells extensively used as a tissue culture model forstudies of sympathoadrenal development. Botulinum toxin inhibits therelease of both types of compounds from both types of cells in vitro,permeabilized (as by electroporation) or by direct injection of thetoxin into the denervated cell. Botulinum toxin is also known to blockrelease of the neurotransmitter glutamate from cortical synaptosomescell cultures.

A neuromuscular junction is formed in skeletal muscle by the proximityof axons to muscle cells. A signal transmitted through the nervoussystem results in an action potential at the terminal axon, withactivation of ion channels and resulting release of the neurotransmitteracetylcholine from intraneuronal synaptic vesicles, for example at themotor endplate of the neuromuscular junction. The acetylcholine crossesthe extracellular space to bind with acetylcholine receptor proteins onthe surface of the muscle end plate. Once sufficient binding hasoccurred, an action potential of the muscle cell causes specificmembrane ion channel changes, resulting in muscle cell contraction. Theacetylcholine is then released from the muscle cells and metabolized bycholinesterases in the extracellular space. The metabolites are recycledback into the terminal axon for reprocessing into further acetylcholine.

What is needed therefore is a non-surgical method for effectivelytreating effectively treating inappropriate, compulsive, ritualisticand/or obsessive behaviors characterized by repetitive, unproductivemotor activity.

SUMMARY

The present invention meets this need and provides methods foreffectively treating inappropriate, compulsive, ritualistic and/orobsessive behaviors characterized by repetitive, unproductive motoractivity with a low dose of a Clostridial toxin.

A method according to my invention can be carried out by administrationof a Clostridial toxin to a patient with an obsessive disorder and/orwith a compulsive disorder. As used herein “obsessive compulsivedisorder” means an obsessive disorder or a compulsive disorder, or adisorder which combines elements of both obsession and compulsion.“Treating” means to alleviate (or to eliminate) at least one symptom,either temporarily or permanently. The Clostridial toxin is preferably abotulinum toxin (as either a complex or as a pure [i.e. about 150 kDamolecule], such as a botulinum toxin A, B, C, D, E, F or G.Administration of the Clostridial toxin can be by a transdermal route(i.e. by application of a Clostridial toxin in a cream, patch or lotionvehicle), subdermal route (i.e. subcutaneous or intramuscular) or by anintradermal route of administration.

A hypothesized physiological reason for the efficacy of my invention, asexplained in greater detail below, is to reduce, inhibit or eliminateparticular sensory input (afferent) from the periphery into the centralnervous system (including to the brain) which sensory input is believedto precede and to be pivotal to the initiation of a repetitive,unproductive motor activity. Such inappropriate sensory input can beattenuated or eliminated by targeting sensory neurons located withinmuscle tissues or that are located in or under the skin with a low doseof a Clostridial toxin.

The dose of a Clostridial toxin used according to the present inventionis much less than the amount of toxin that would be used to paralyze amuscle (and is even less than the amount of the toxin used to reduce arigid muscle tone by a clinically significant amount), since the intentof a method according to the present invention is not to paralyze amuscle or to reduce the tone of a rigid muscle, but to reduce anundesirable sensory output from sensory neurons located in or a muscleor in or under the skin. Additionally, the low dose of the Clostridialtoxin is selected with a volume to preferably achieve a toxindistribution to multiple sites of undesirable afferent sensory signals,such as from spindle fibers or secretory cells in the skin orsubdermally.

Excluded from the scope of present invention is administration (as byintramuscular injection) of a Clostridial toxin (such as a botulinumtoxin) into any neck muscles (such as into the splenii muscles) of apatient because such a local administration of toxin can result,particularly in adolescent patients, in poor head orientation (“floppyhead”), prolonged neck pain, neck weakness and/or neck stiffness and/orexacerbation of a pre-existing neck or spinal injury (often due to thetic itself). Additionally, the complex neurological nature of Tourette'ssyndrome and the contradictory state of the art with regard toTourette's syndrome tics contraindicate use of a botulinum toxin totreat a symptom of Tourette's syndrome. Thus, treatment of focaldystonic neck tics, such as the neck tics associated with Tourette'ssyndrome, is excluded from the scope of the present invention, as beingbetter treated by head restraints, behavioral modification therapyand/or proven pharmacologic agents, such as TCAs or SSRIs.

Thus, my invention is a pharmacologic method for treating inappropriate,compulsive, ritualistic and/or obsessive behaviors characterized byrepetitive, unproductive motor activity, which are not neck tics. Myinvention can be practised by administering a low dose of a Clostridialtoxin to the muscle or muscle group which appears to initiates therepetitive, unproductive motor activity (i.e. to treat repetitive handwashing) or to the skin in the areas of picking or hair pulling ifdiffusion effects of botulinum toxin do not contraindicate such use incertain areas of the face. Alternately my invention can be practised byadministering a low dose of a Clostridial toxin to intradermal orsubdermal sensory neurons which apparently generate an urge, itch orsensation which precedes the repetitive motor activity (i.e. skinpicking). As explained above, my invention is not suitable for thetreatment for any neck tics (whether motor or vocal), and additionallydoes not encompass treatment of any muscle spasms. “Low dose” means anamount of the Clostridial toxin (such as a botulinum toxin) which issufficient to inhibit a sensory output from a muscle to the CNS, butwhich is insufficient to cause either clinically significant muscleparalysis, weakness or hypotonicity.

The following definitions also apply herein:

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means±10% of the numerical value orrange recited or claimed.

“Alleviating” means a reduction in the occurrence of the disorder. Thus,alleviating includes some reduction (so that the disorder is practisedfor fewer than, or appears in fewer than, than six hours out of atwenty-four hour period), significant reduction (so that the disorder ispractised for fewer than, or appears in fewer than, three hours out of atwenty-four hour period), near total reduction (so that the disorder ispractised for fewer than, or appears in fewer than, one hour out of atwenty-four hour period), and total reduction of the disorder. Analleviating effect may not appear clinically for between 1 to 7 daysafter administration of a Clostridial toxin to a patient.

“Botulinum toxin” means a botulinum neurotoxin as either pure toxin orcomplex, and excludes botulinum toxins which are not neurotoxins such asthe cytotoxic botulinum toxins C₂ and C₃.

“Disorder” means an inappropriate, compulsive, ritualistic and/orobsessive behaviors characterized by repetitive, unproductive motoractivity, which are not neck tics. Specific obsessive compulsivedisorders are defined as set forth in the DSM-IVR.

“Local administration” means peripheral administration (i.e. by asubcutaneous, intramuscular, subdermal or transdermal route) of apharmaceutical agent to or to the vicinity of a muscle or of a subdermallocation of a patient by a non-systemic route. Thus, localadministration excludes systemic (i.e. to the blood circulation system)routes of administration, such as intravenous or oral administration.Peripheral administration means administration to the periphery (i.e. toa location on or within a limb, trunk or head of a patient) as opposedto a visceral or gut (i.e. to the viscera) administration. An example oflocal administration is intramuscular injection of a pharmaceuticalagent to a head or facial muscle or subdermal location of a patient.

Methods for treating a disorder characteristic by inappropriate,compulsive, ritualistic and/or obsessive behaviors characterized byrepetitive, unproductive motor activity with a low dose of a Clostridialtoxin comprise the step of local administration of Clostridialneurotoxin to a patient. The Clostridial neurotoxin is administered in atherapeutically effective amount to alleviate at least one symptom ofthe disorder.

A suitable Clostridial neurotoxin may be a neurotoxin made by abacterium, for example, the neurotoxin may be made from a Clostridiumbotulinum, Clostridium butyricum, or Clostridium beratti. In certainembodiments of the invention, the disorders are treated by intramuscularadministration a botulinum toxin to the patient. The botulinum toxin maybe a botulinum toxin type A, type B, type C₁, type D, type E, type F, ortype G. The effects of the botulinum toxin may persist for between about1 month and 5 years. The botulinum neurotoxin can be a recombinantlymade botulinum neurotoxins, such as botulinum toxins produced by E.coli. In addition or alternatively, the botulinum neurotoxin can be amodified neurotoxin, that is a botulinum neurotoxin which has at leastone of its amino acids deleted, modified or replaced, as compared to anative or the modified botulinum neurotoxin can be a recombinantproduced botulinum neurotoxin or a derivative or fragment thereof.

The botulinum neurotoxin is administered to a peripheral site that isbelieved to be involved in the disorder being treated. The botulinumneurotoxin can be administered to a muscle which appears to initiate thedisorder and can alleviate the symptoms within a few hours or within afew days after administration.

A method for treating an eye poking disorder according to the presentinvention can comprise the step of local administration of a botulinumtoxin to a patient with an eye poking disorder to thereby alleviate theeye poking disorder. The botulinum toxin can be selected from the groupconsisting of botulinum toxin types A, B, C, D, E, F and G. Botulinumtoxin type A is a preferred botulinum toxin. The botulinum toxin can beadministered in an amount of between about 1 unit and about 1,500 unitsand the alleviation of the disorder can persists for between about 1month and about 5 years. The local administration of the botulinum toxincan be to a periocular muscle or to a hand or forearm muscle. The localadministration can be by intramuscular injection. Alternately, the localadministration of the botulinum toxin can be to a dermal location or toa muscle location from which the patient perceives the existence of apremonitory sensation, which leads to the generation of the disorder, toarise.

A detailed embodiment of my invention can comprise a method for treatingan eye poking disorder, the method comprising a step of localadministration to a periocular muscle of a patient with an eye pokingdisorder of between about 1 unit and about 2,500 units of a botulinumtoxin (for example between about 1-50 units of a botulinum toxin type Aor between about 50 to 2,500 units of a botulinum toxin type B), therebyalleviating the eye poking disorder for between about 1 month and about5 years.

A method for treating a body rocking disorder can comprise the step oflocal administration of a botulinum toxin to a patient with a bodyrocking disorder, thereby alleviating the body rocking disorder. Herethe local administration of the botulinum toxin can be to a buttocksmuscle or to an arm muscle or to lower back and trunk muscles dependingon the clinical pattern of movement that forms the compulsion.

A detailed embodiment of my invention can comprise a method for treatinga body rocking disorder, the method comprising a step of localadministration to a muscle of a patient with a body rocking disorder ofbetween about 1 unit and about 1,500 units of a botulinum toxin type A,thereby alleviating the body rocking disorder for between about 1 monthand about 5 years.

A method for treating a finger or nail biting disorder can comprise themethod comprising a step of local administration of a botulinum toxin toa patient with a finger biting or nail disorder, thereby alleviating thefinger or nail biting disorder. The local administration of thebotulinum toxin can be to a hand muscle or to an arm muscle, which havecontrol over the movement of the finger or hand and from which theundesirable sensory stimuli arises.

A detailed embodiment of my invention can comprise a method for treatinga finger biting disorder, the method comprising a step of localadministration to a hand muscle of a patient with a finger bitingdisorder of between about 1 unit and about 2,500 units of a botulinumtoxin (for example between about 1-50 units of a botulinum toxin type Aor between about 50 to 2,500 units of a botulinum toxin type B), therebyalleviating the finger biting disorder for between about 1 month andabout 5 years.

A method for treating a counting disorder can comprise the step of localadministration of a botulinum toxin to a patient with a countingdisorder, thereby alleviating the counting disorder. The localadministration of the botulinum toxin can be to the set of muscles whichupon observation of the patient are correlated with that countingbehavior, i.e. ritual counting associated with hand motions or fingercounting, can be treated by toxin injection into the muscles associatedwith control over the ritualized motor activity. The toxinadministration can also be to a peri ocular muscle (or to a head muscle,such as a facial muscle) if the counting behavior is associated withabnormal eye movement, and to the lower or upper legs if the behavior isassociated with the obsessive counting of steps.

A detailed embodiment of my invention can comprise a method for treatinga counting disorder by the step of local administration to a muscle of apatient with a counting disorder of between about 1 unit and about 1,500units of a botulinum toxin (for example between about 1-50 units of abotulinum toxin type A or between about 50 to 2,500 units of a botulinumtoxin type B) thereby alleviating the counting disorder for betweenabout 1 month and about 5 years.

A method for treating a checking disorder can comprise the step of localadministration of a botulinum toxin to a patient with a checkingdisorder, thereby alleviating the checking disorder. The localadministration of the botulinum toxin Is determined by analysis of themotoric patterns exhibited by the patient in the ritualized checkingbehavior, for example for the disorder of repeatedly checking a lockeddoor, toxin administration is into the muscles of the forearm associatedwith grasping and turning the knob of the door. Complex pattern ofchecking are assessed prior to determining the sites of toxin injection,and toxin administration can be to head or facial muscles.

A detailed embodiment of my invention can comprise a method for treatinga checking disorder, the method comprising a step of localadministration to a head muscle of a patient with a checking disorder ofbetween about 1 unit and about 1,500 units of a botulinum toxin type A,thereby alleviating the checking disorder for between about 1 month andabout 5 years.

DESCRIPTION

The present invention is based on the discovery that peripheraladministration of a low dose of a Clostridial toxin (such as a botulinumtoxin) can provide effective treatment or relief of inappropriate,compulsive, ritualistic and/or obsessive behaviors characterized byrepetitive, unproductive motor activity. Thus, a botulinum toxin (suchas a botulinum toxin serotype A, B, C₁, D, E, F or G) can be injectedinto a muscle which initiates (or acts to recruit other muscles to) theundesirable repetitive behavior to thereby suppress and treat such anundesirable and/or self injurious motoric behavioral characteristic.Alternately, the botulinum toxin can be administered to an intradermalor subdermal sensory neuron thereby suppress and treat such anundesirable and/or self injurious motoric behavioral characteristic.

Without wishing to be bound by theory a physiological mechanism can beproposed for the efficacy of the present invention. It is known thatmuscles have a complex system of innervation and sensory output. Thus,anterior motor neurons located in each segment of the anterior horns ofthe spinal cord gray matter give rise to efferent alpha motor neuronsand efferent gamma motor neurons that leave the spinal cord by way ofthe anterior roots to innervate skeletal (extrafusal) muscle fibers. Thealpha motor neurons cause contraction of extrafusal skeletal musclefibers while the gamma motor neurons innervate the intrafusal fibers ofskeletal muscle. As well as excitation by these two type of efferentanterior motor neuron projections, there are additional, afferentsensory neurons which project from muscle spindle and golgi tendonorgans and act to transmit information regarding various muscleparameter status to the spinal cord, cerebellum and cerebral cortex.These afferent motor neurons which relay sensory information from themuscle spindle include type Ia and type II sensory afferent neurons. Seee.g. pages 686-688 of Guyton A. C. et al., Textbook of MedicalPhysiology, W.B. Saunders Company 1996, ninth edition.

Significantly, it has been determined that a botulinum toxin can act toreduce transmission of sensory information from muscle type Ia afferentneurons. Aoki, K., Physiology and pharmacology of therapeutic botulinumneurotoxins, in Kreyden, O., editor, Hyperhydrosis and botulinum toxinin dermatology, Basel, Karger; 2002; 30: pages 107-116, at 109-110. Andit has been hypothesized that botulinum toxin can have a direct effectupon muscle cell sensory afferents and modify signals from theseafferents to the central nervous system. See e.g. Brin, M., et al.,Botulinum toxin type A: pharmacology, in Mayer N., editor, Spasticity:etiology, evaluation, management and the role of botulinum toxin, 2002;pages 110-124, at 112-113; Cui, M., et al., Mechanisms of theantinociceptive effect of subcutaneous BOTOX®: inhibition of peripheraland central nociceptive processing, Naunyn Schmiedebergs Arch Pharmacol2002; 365 (supp 2): R17; Aoki, K., et al., Botulinum toxin type A andother botulinum toxin serotypes: a comparative review of biochemical andpharmacological actions, Eur J. Neurol 2001: (suppl 5); 21-29. Thus, ithas been demonstrated that botulinum toxin can cause an altered sensoryoutput from muscle to CNS and brain.

Importantly, the sensory neurons from which afferent output is to beinhibited by a method according to the present invention need not belocated on or within a muscle, but can be in an intradermal or subdermallocation.

It can be postulated that obsessive-compulsive disorders are due todisinhibition of a central nervous system control process. Thus, adisinhibition reverberatory circuit may exist between the head of thecaudate nucleus and the thalamus and between the thalamus and thefrontorbito neurons which is sensitive to signals arising fromperipheral sensory information afferent from muscle neurons.Administration of a botulinum toxin to a muscles or skin to reducesensory output from the muscle can permit the brain to regain adequateinhibition control of the obsessive-compulsive disorder motor behaviors,by preventing central generation of a premonitory urge to carry out theobsessive-compulsive disorder behavior. Notably, it has been reportedthat local administration of a botulinum toxin to neck muscles canapparently act to reduce generation of the premonitory urge associatedwith some Tourette's syndrome tics. Jankovic, J., Botulinum toxin in thetreatment of tics associated with Tourette's syndrome, Neurology 1993April; 43 (4 Supp 2): A310; Jankovic, J., Botulinum toxin in thetreatment of dystonic tics, Mov Disord 1994 May; 9(3): 347-9, and;Krauss J., et al., Severe motor tics causing cervical myelopathy inTourette's syndrome, Mov Disord 1996; 11(5): 563-6. Additionally, aspreviously discussed relatively high (paralytic effect) thigh muscledoses of a botulinum toxin have been used to treat restless legsyndrome, and injection of botulinum toxin into the chewing muscle hasbeen used to treat the lip, tongue and finger biting behaviors of LeschNyhan syndrome.

It is my hypothesis that signals transmitted by afferent nerves whichinnervate muscles (i.e. muscle spindle fibers and muscle pain fibers) orfrom sensory structures in the skin or subdermally induce a sensorystate which contributes in susceptible individuals to the generation ofobsessive-compulsive disorder behaviors. That is, afferent signal frommuscles or skin structures provide sensory information to the brainwhich then leads to the generation of a complex motor output insusceptible individuals, such as the self mutilation, obsessive handwashing, hair pulling, or other repetitive behaviors ofobsessive-compulsive disorder. Thus, a local administration of a lowdose of a botulinum toxin to muscle spindle fibers, pain fibers or othersensors in or in the vicinity of a muscle can act to alter the neuralsignal afferent output from these muscles to the brain and therebydecreasing neural (to brain) input and inhibit the undesirableobsessive-compulsive disorder behavior by preventing generation of apremonitory urge.

Important elements of my invention are firstly that is practised by useof a local administration of low dose of a botulinum toxin. The selectedlow dose causes neither muscle paralysis, weakness nor musclehypotonicity. Secondly, the invention is practised by localadministration of the low dose of the botulinum toxin to the muscle orto the muscle group which initiates the undesirable motor behavior. Forexample, with regard to obsessive finger biting the botulinum toxin isadministered to the hand or forearm muscles. With regard to ritualisticchecking and counting behaviors, the botulinum toxin is administered tothe head muscles, such as scalp, forehead or facial muscles on the basisthat such behaviors are initiated by sensory input from such muscle.

Conditions treatable by the present invention include skin picking, hairpulling, head banging, body rocking, counting, checking, and hoardingbehaviors which are inappropriate, compulsive, ritualistic and/orobsessive behaviors characterized by repetitive, unproductive motoractivity, which are not neck tics.

In compulsive skin picking there is often a psychotic sensation of skincrawling with the common description of perception of movementhypodermally. This sensation may very well be due to premonitory urgestriggered by skin associated tiny muscle structures such as the arrectorpili muscles of hair follicles, smooth muscle vasculature of the dermisor neural sensory structures within the skin. Thus, hypodermal(subcutaneous) injection into the dermis of a Clostridial toxin can beexpected to focally relieve or block this sensation for several months.

Other disorders treatable by a method within the scope of the presentinvention include conditions with stereotypic movements such as DownsSyndrome, pervasive developmental disorder, developmental movementdisorder, autism (hand/finger movement subtype), Asperger's Syndrome(hand/finger movement type) and Rhett's Syndrome (handwashingmovements).

The administration of the Clostridial toxin is carried out so as totarget, for example, focal motoric movements of obsessive compulsivedisorders. Thus, for repetitive hand washing behavior the toxin can beinjected into the forearm muscles associated with washing movements, orinto the hands based upon a pattern for the treatment of hyperhydrosisor a combination thereof. Treatment sites and doses can be selectedbased upon the muscles which initiate the observed movement at doseswhich do not produce significant muscle weakness. Thus, an injectionpattern is selected to focus on the muscles which initiate the observedinappropriate movements.

The amount of the Clostridial toxin administered according to a methodwithin the scope of the disclosed invention can vary according to theparticular disorder being treated, its severity and other variouspatient variables including size, weight, age, and responsiveness totherapy. To guide the practitioner, typically, no less than about 1 unitand no more than about 25 units of a botulinum toxin type A (such asBOTOX®) is administered per injection site, per patent treatmentsession. For a botulinum toxin type A such as DYSPORT®, no less thanabout 2 units and no more about 125 units of the botulinum toxin type Aare administered per injection site, per patent treatment session. For abotulinum toxin type B such as MYOBLOC®, no less than about 40 units andno more about 1500 units of the botulinum toxin type B are administeredper injection site, per patent treatment session. Less than about 1, 2or 40 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively) can fail toachieve a desired therapeutic effect, while more than about 25, 125 or1500 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively) can result insignificant muscle hypotonicity, weakness and/or paralysis, all of whichare undesirable outcomes in a practise of the disclosed inventionbecause the purpose of my invention is to treat inappropriatecompulsive, ritualistic and/or obsessive behaviors characterized byrepetitive, unproductive motor activity, which are not neck tics, with alow dose of a Clostridial toxin to the muscle or muscle group whichappears to initiates the repetitive, unproductive motor activity, thedose being sufficient to inhibit a sensory output from a muscle to theCNS, but insufficient to cause either significant muscle paralysis,weakness or hypotonicity.

More preferably: for BOTOX® no less than about 2 units and no more about20 units of a botulinum toxin type A; for DYSPORT® no less than about 4units and no more than about 100 units, and; for MYOBLOC®, no less thanabout 80 units and no more than about 1000 units are, respectively,administered per injection site, per patent treatment session.

Most preferably: for BOTOX® no less than about 5 units and no more about15 units of a botulinum toxin type A; for DYSPORT® no less than about 20units and no more than about 75 units, and; for MYOBLOC®, no less thanabout 200 units and no more than about 750 units are, respectively,administered per injection site, per patent treatment session. It isimportant to note that there can be multiple injection sites (i.e. apattern of injections) for each patient treatment session.

Although examples of routes of administration and dosages are provided,the appropriate route of administration and dosage are generallydetermined on a case by case basis by the attending physician. Suchdeterminations are routine to one of ordinary skill in the art (see forexample, Harrison's Principles of Internal Medicine (1998), edited byAnthony Fauci et al., 14^(th) edition, published by McGraw Hill). Forexample, the route and dosage for administration of a neurotoxinaccording to the present disclosed invention can be selected based uponcriteria such as the solubility characteristics of the neurotoxin chosenas well as the intensity of the disorder as perceived by the patient.

The present invention is based on the discovery that peripheraladministration of a Clostridial toxin can provide significant and longlasting relief from a variety of different obsessive-compulsivedisorders. Peripheral administration permits a Clostridial toxin to belocally administered at a site, at or near a patient's muscle that has adirect effect on the neurons involved in the disorders,

The Clostridial toxins used in accordance with the invention disclosedherein can inhibit transmission of chemical or electrical signalsbetween select neuronal groups that are involved in generation of anobsessive-compulsive disorder. The Clostridial toxins preferably are notcytotoxic to the cells that are exposed to the Clostridial toxin. TheClostridial toxin can inhibit neurotransmission by reducing orpreventing exocytosis of neurotransmitter from the neurons exposed tothe Clostridial toxin. Or, the applied Clostridial toxins may reduceneurotransmission by inhibiting the generation of action potentials ofthe neurons exposed to the toxin. The suppressive effects provided bythe Clostridial toxin should persist for a relatively long period oftime, for example, for more than two months, and potentially for severalyears.

Examples of Clostridial toxins within the scope of the present inventioninclude neurotoxins made by Clostridium botulinum, Clostridium butyricumand Clostridium beratti species. In addition, the botulinum toxins usedin the methods of the invention may be a botulinum toxin selected from agroup of botulinum toxin types A, B, C, D, E, F, and G. In oneembodiment of the invention, the botulinum neurotoxin administered tothe patient is botulinum toxin type A. Botulinum toxin type A isdesirable due to its high potency in humans, ready availability, andknown use for the treatment of skeletal and smooth muscle disorders whenlocally administered by intramuscular injection. The present inventionalso includes the use of (a) Clostridial neurotoxins obtained orprocessed by bacterial culturing, toxin extraction, concentration,preservation, freeze drying, and/or reconstitution; and/or (b) modifiedor recombinant neurotoxins, that is neurotoxins that have had one ormore amino acids or amino acid sequences deliberately deleted, modifiedor replaced by known chemical/biochemical amino acid modificationprocedures or by use of known host cell/recombinant vector recombinanttechnologies, as well as derivatives or fragments of neurotoxins somade. These neurotoxin variants retain the ability to inhibitneurotransmission between or among neurons, and some of these variantsmay provide increased durations of inhibitory effects as compared tonative neurotoxins, or may provide enhanced binding specificity to theneurons exposed to the neurotoxins. These neurotoxin variants may beselected by screening the variants using conventional assays to identifyneurotoxins that have the desired physiological effects of inhibitingneurotransmission.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient.

Although the composition may only contain a single type of neurotoxin,such as botulinum toxin type A, as the active ingredient to suppressneurotransmission, other therapeutic compositions may include two ormore types of neurotoxins, which may provide enhanced therapeuticeffects of the disorders. For example, a composition administered to apatient may include botulinum toxin type A and botulinum toxin type B.Administering a single composition containing two different neurotoxinsmay permit the effective concentration of each of the neurotoxins to belower than if a single neurotoxin is administered to the patient whilestill achieving the desired therapeutic effects. The compositionadministered to the patient may also contain other pharmaceuticallyactive ingredients, such as, protein receptor or ion channel modulators,in combination with the neurotoxin or neurotoxins. These modulators maycontribute to the reduction in neurotransmission between the variousneurons. For example, a composition may contain gamma aminobutyric acid(GABA) type A receptor modulators that enhance the inhibitory effectsmediated by the GABA_(A) receptor. The GABA_(A) receptor inhibitsneuronal activity by effectively shunting current flow across the cellmembrane. GABA_(A) receptor modulators may enhance the inhibitoryeffects of the GABA_(A) receptor and reduce electrical or chemicalsignal transmission from the neurons. Examples of GABA_(A) receptormodulators include benzodiazepines, such as diazepam, oxaxepam,lorazepam, prazepam, alprazolam, halazeapam, chordiazepoxide, andchlorazepate. Compositions may also contain glutamate receptormodulators that decrease the excitatory effects mediated by glutamatereceptors. Examples of glutamate receptor modulators include agents thatinhibit current flux through AMPA, NMDA, and/or kainate types ofglutamate receptors. The compositions may also include agents thatmodulate dopamine receptors, such as antipsychotics, norepinephrinereceptors, and/or serotonin receptors. The compositions may also includeagents that affect ion flux through voltage gated calcium channels,potassium channels, and/or sodium channels. Thus, the compositions usedto treat obsessive compulsive disorders may include one or moreneurotoxins, such as botulinum toxins, in addition to ion channelreceptor modulators that may reduce neurotransmission.

The neurotoxin may be administered by any suitable method as determinedby the attending physician. The methods of administration permit theneurotoxin to be administered locally to a selected target tissue.Methods of administration include injection of a solution or compositioncontaining the neurotoxin, as described above, and include implantationof a controlled release system that controllably releases the neurotoxinto the target tissue. Such controlled release systems reduce the needfor repeat injections. Diffusion of biological activity of a botulinumtoxin within a tissue appears to be a function of dose and can begraduated. Jankovic J., et al Therapy With Botulinum Toxin, MarcelDekker, Inc., (1994), page 150. Thus, diffusion of botulinum toxin canbe controlled to reduce potentially undesirable side effects that mayaffect the patient's cognitive abilities. For example, the neurotoxinmay be administered so that the neurotoxin primarily effects neuralsystems believed to be involved in the obsessive compulsive disorder,and does not have negatively adverse effects on other neural systems.

A polyanhydride polymer, GLIADEL® (Stolle R&D, Inc., Cincinnati, Ohio) acopolymer of poly-carboxyphenoxypropane and sebacic acid in a ratio of20:80 has been used to make implants, and has been intracraniallyimplanted to treat malignant gliomas. Polymer and BCNU can beco-dissolved in methylene chloride and spray-dried into microspheres.The microspheres can then be pressed into discs 1.4 cm in diameter and1.0 mm thick by compression molding, packaged in aluminum foil pouchesunder nitrogen atmosphere and sterilized by 2.2 megaRads of gammairradiation. The polymer permits release of carmustine over a 2-3 weekperiod, although it can take more than a year for the polymer to belargely degraded. Brem, H., et al, Placebo-Controlled Trial of Safetyand Efficacy of Intraoperative Controlled Delivery by BiodegradablePolymers of Chemotherapy for Recurrent Gliomas, Lancet 345;1008-101:1995.

Implants useful in practicing the methods disclosed herein may beprepared by mixing a desired amount of a stabilized neurotoxin (such asnon-reconstituted BOTOX®) into a solution of a suitable polymerdissolved in methylene chloride. The solution may be prepared at roomtemperature. The solution can then be transferred to a Petri dish andthe methylene chloride evaporated in a vacuum desiccator. Depending uponthe implant size desired and hence the amount of incorporatedneurotoxin, a suitable amount of the dried neurotoxin incorporatingimplant is compressed at about 8000 p.s.i. for 5 seconds or at 3000p.s.i. for 17 seconds in a mold to form implant discs encapsulating theneurotoxin. See e.g. Fung L. K. et al., Pharmacokinetics of InterstitialDelivery of Carmustine 4-Hydroperoxycyclophosphamide and Paclitaxel Froma Biodegradable Polymer Implant in the Monkey Brain, Cancer Research 58;672-684:1998.

Local administration of a Clostridial toxin, such as a botulinum toxin,can provide a high, local therapeutic level of the toxin. A controlledrelease polymer capable of long term, local delivery of a Clostridialtoxin to a target muscle permits effective dosing of a target tissue. Asuitable implant, as set forth in U.S. Pat. No. 6,306,423 entitled“Neurotoxin Implant”, allows the direct introduction of achemotherapeutic agent to a target tissue via a controlled releasepolymer. The implant polymers used are preferably hydrophobic so as toprotect the polymer incorporated neurotoxin from water induceddecomposition until the toxin is released into the target tissueenvironment.

Local administration of a botulinum toxin, according to the presentinvention, by injection or implant to a target tissue provides asuperior alternative to systemic administration of pharmaceuticals topatients to alleviate the symptoms associated with the disorderstreated.

The amount of a Clostridial toxin selected for local administration to atarget tissue according to the present disclosed invention can be variedbased upon criteria such as the disorder being treated, its severity,the extent of muscle tissue to be treated, solubility characteristics ofthe neurotoxin toxin chosen as well as the age, sex, weight and healthof the patient. For example, the extent of the area of muscle tissueinfluenced is believed to be proportional to the volume of neurotoxininjected, while the quantity of the suppressant effect is, for most doseranges, believed to be proportional to the concentration of aClostridial toxin administered. Methods for determining the appropriateroute of administration and dosage are generally determined on a case bycase basis by the attending physician. Such determinations are routineto one of ordinary skill in the art (see for example, Harrison'sPrinciples of Internal Medicine (1998), edited by Anthony Fauci et al.,14^(th) edition, published by McGraw Hill).

Significantly, a method within the scope of the present invention canprovide improved patient function. “Improved patient function” can bedefined as an improvement measured by factors such as a reduced pain,reduced time spent in bed, increased ambulation, healthier attitude,more varied lifestyle and/or healing permitted by normal muscle tone.Improved patient function is synonymous with an improved quality of life(QOL). QOL can be assessed using, for example, the known SF-12 or SF-36health survey scoring procedures. SF-36 assesses a patient's physicaland mental health in the eight domains of physical functioning, rolelimitations due to physical problems, social functioning, bodily pain,general mental health, role limitations due to emotional problems,vitality, and general health perceptions. Scores obtained can becompared to published values available for various general and patientpopulations.

EXAMPLES

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat conditions within thescope of the present invention and are not intended to limit the scopeof the invention. In the following examples various modes ofnon-systemic administration of a Clostridial neurotoxin can be carriedout. For example, by intramuscular injection, subcutaneous injection orby implantation of a controlled release implant.

Example 1 Botulinum Toxin Type A Therapy for Head Banging

A 15 year old male bangs his head on walls and on his school deskwithout obvious triggers. He reports 20-25 head banging episodes a day.Upon examination he relates that he is lonely and feels an urge to, andgratification upon, carrying out the chronic head banging. His foreheadis bruised and tender to the touch. The patient is treated byintramuscular injection of 5 units of a botulinum toxin type A (i.e.BOTOX®) into the forehead muscles bilaterally at two different locations(10 units toxin total). Within 1-7 days after toxin administration thepatient report that he now banging his head only once or twice a day andsuch an alleviation of his condition persists for 4-6 months. Forextended therapeutic relief (1 to 5 years), one or more polymericimplants incorporating a suitable quantity of a botulinum toxin type Acan be placed at the target tissue site.

A botulinum toxin type B, C, D, E, F or G can be substituted for thebotulinum toxin type A used above, for example by use of 250 units of abotulinum toxin type B.

Example 2 Botulinum Toxin Type A Therapy for Repetitive Hand Washing

A 46 year old male presents with red, chapped hands. He relatescompulsive washing of his hands for 6 to 8 hours a day, often afternormal hygiene activities. The patient is treated by intramuscularinjection of 5 units of a botulinum toxin type A (i.e. BOTOX®) into theforearm muscles bilaterally at two different locations (10 units toxin,per arm). Within 1-7 days after toxin administration the patient reportthat he is washing his hands now for less than one hour a day andalleviation of his condition persists for 4-6 months. For extendedtherapeutic relief (1 to 5 years), one or more polymeric implantsincorporating a suitable quantity of a botulinum toxin type A can beplaced at the target tissue site.

Example 3 Botulinum Toxin Type B Therapy for Repetitive Hand Washing

A 22 year old female presents with red, chapped hands. She relatescompulsive washing of hers hands for 7 to 9 hours a day, often afternormal hygiene activities. She relates perception in her hands of anurge to wash them. The patient is treated by intramuscular injection of225 units of a botulinum toxin type B (i.e. MYOBLOC®) into the palm ofeach of her hands. Within 1-7 days after toxin administration thepatient report that she is washing her hands now for less than one halfhour a day and alleviation of the condition persists for 4-6 months. Forextended therapeutic relief (1 to 5 years), one or more polymericimplants incorporating a suitable quantity of a botulinum toxin type Bcan be placed at the target tissue site.

A botulinum toxin type C, D, E, F or G can be substituted for thebotulinum toxin type A or B used in the examples above.

Example 4 Botulinum Toxin Therapy for Trichotillomania

A sixteen year old girl with normal intelligence is referred by herdermatologist and examined for several, irregular bald patches on herhead. The hair loss is on the contralateral side of the dominant handand the affected areas include broken hairs of varying lengths with skindiscoloration secondary to rubbing the scalp. The child admits topulling her hair because “I'm depressed.” Adrenal function is normal andtrichotillomania is diagnosed. The patient's trichotillomania showednominal response to antidepressant medication, including tricyclicantidepressants (desipramine and imipramine), as these medicationsresulted in a brief 2-3 day remission of the hair pulling. Othertherapeutic interventions included cognitive behavioral therapy andcounseling, both of which were unsuccessful, despite attendance. Thechild is treated by intramuscular injection of 5 units of a botulinumtoxin type A (i.e. BOTOX®) into the frontalis and occipitalis muscles(10 units toxin, per treatment session). Alternately, so as to achieve awider distribution of the botulinum toxin, 100 units of a botulinumtoxin type A in 5 ml of saline can be injected into multiple (about 20sites) scalp locations. Within 1-7 days after toxin administration thepatient report that she has stopped pulling her hair and alleviation ofher condition persists for 4-6 months. For extended therapeutic relief(1 to 5 years), one or more polymeric implants incorporating a suitablequantity of a botulinum toxin type A can be placed at the target tissuesite.

A botulinum toxin type B, C, D, E, F or G can be substituted for thebotulinum toxin type A used above, for example by use of 250 units of abotulinum toxin type B.

Example 5 Botulinum Toxin Type A Therapy for Dermatillomania

A 57 year old married woman is examined for chronic skin picking overthe last 3 years to her arms and legs, never leaving the lesions alonelong enough to heal. Prior to clinical presentation she has triedalternative treatment approaches for the picking, including acupuncture,dermatology consultation, and group therapy. She picks with herfingernails and often ingests the scabs after removal. She relates anurge which builds up and which is relieved by the picking. Her conditionis recalcitrant to behavior modification therapy, fluoxetine andvenlafaxine. After informed consent, 4 units of a botulinum toxin type A(i.e. BOTOX®) are injected subdermally at the locations of the chronicskin picking. Alternately, so as to achieve a wider distribution of thebotulinum toxin, 100 units of a botulinum toxin type A in 5 ml of salinecan be injected into multiple (about 20) sites of the skin picking.Within 1-7 days after toxin administration the patient has stoppedpicking her skin and alleviation of her condition persists for 4-6months. For extended therapeutic relief (1 to 5 years), one or morepolymeric implants incorporating a suitable quantity of a botulinumtoxin type A can be placed at the target tissue site.

Example 6 Botulinum Toxin Type B Therapy for Dermatillomania

A 26 year old, divorced, college educated man seeks treatment for hischronic, self injurious skin picking. He describes an awareness ofclogged pores on his face, especially around his nose and chin which hetries to unclog with his fingernails. The target of his skin pickingincludes “raised skin” as well as healthy skin. Skin picking episodesend when his skin becomes inflamed or bleeding. He reports about 20 skinpicking episodes every day, with each episode lasting 1 to five minutes.He relates feeling tension or nervousness build up before the skinpicking and relief after he has picked. 200 units of a botulinum toxintype B is are injected subdermally at three separate the locations ofthe chronic facial skin picking. Alternately, so as to achieve a widerdistribution of the botulinum toxin, 5000 units of a botulinum toxintype B in 5 ml of saline can be injected into multiple (about 20) sitesof the skin picking. Within 1-7 days after toxin administration thepatient has stopped picking his skin and alleviation of the conditionpersists for 4-6 months. For extended therapeutic relief (1 to 5 years),one or more polymeric implants incorporating a suitable quantity of abotulinum toxin type B can be placed at the target tissue site.

A botulinum toxin type C, D, E, F or G can be substituted for thebotulinum toxin type A or B used in the examples above.

Example 7 Botulinum Toxin Type A Therapy for Finger Biting

An eight year old boy with mild mental retardation bites his fingershands regularly and his fingers have become ulcerated. He mother reportsthat he will bite his fingers continuously unless restrained. Thepatient is treated by intramuscular injection of 3 units of a botulinumtoxin type A (i.e. BOTOX®) into the base of each finger on each hand.Alternately, the forearm muscles can be injected bilaterally with 10units of the botulinum toxin. Within 1-7 days after toxin administrationthe finger biting has completely subsided and resolved. His fingers healand this alleviation of his condition persists for 4-6 months. Forextended therapeutic relief (1 to 5 years), one or more polymericimplants incorporating a suitable quantity of a botulinum toxin type Acan be placed at the target tissue site.

A botulinum toxin type B, C, D, E, F or G can be substituted for thebotulinum toxin type A used above, for example by use of 250 units of abotulinum toxin type B.

Example 8 Botulinum Toxin Type A Therapy for Pruritis Associated withPsychosis

A 26 year old married female is referred for pharmacologicallyrecalcitrant skin itching which is described to feel as if an insect iscrawling under her skin. On repeated instances when not restrained shehas cut herself to “let out the bugs”. Auditory and visualhallucinations are also present. The patient is treated 4 units of abotulinum toxin type A (i.e. BOTOX®) are injected subdermally at thelocations of the chronic skin itching. Alternately, so as to achieve awider distribution of the botulinum toxin, 100 units of a botulinumtoxin type A in 5 ml of saline can be injected into multiple (about 20)sites of the perceived skin itching. Within 1-7 days after toxinadministration the patient reports relief from the skin itching andalleviation of her condition persists for 4-6 months. For extendedtherapeutic relief (1 to 5 years), one or more polymeric implantsincorporating a suitable quantity of a botulinum toxin type A can beplaced at the target tissue site.

Although the present invention has been described in detail with regardto certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, a wide variety of neurotoxins can be effectively used inthe methods of the present invention. Additionally, the presentinvention includes peripheral administration methods to alleviate adisorder wherein two or more neurotoxins, such as two or more botulinumtoxins, are administered concurrently or consecutively. For example,botulinum toxin type A can be administered until a loss of clinicalresponse or neutralizing antibodies develop, followed by administrationof botulinum toxin type B. Alternately, a combination of any two or moreof the botulinum serotypes A-G can be locally administered to controlthe onset and duration of the desired therapeutic result. Furthermore,non-neurotoxin compounds can be administered prior to, concurrently withor subsequent to administration of the neurotoxin to proved adjuncteffect such as enhanced or a more rapid onset of denervation before theneurotoxin, such as a botulinum toxin, begins to exert its therapeuticeffect.

A method for treating a disorder according to the invention disclosedherein has many benefits and advantages, including the following:

1. the symptoms can be dramatically reduced.

2. the symptoms of an obsessive-compulsive disorder can be reduced forfrom about two to about six months per injection of neurotoxin and forfrom about one year to about five years upon use of a controlled releaseneurotoxin implant.

3. the injected or implanted neurotoxin exerts an intramuscular targettissue site specific suppression of neuronal activity.

4. the injected or implanted Clostridial neurotoxin shows little or notendency to diffuse or to be transported away from the intramuscular (orintradermal or subdermal) injection or implantation site.

5. few or no significant undesirable side effects occur fromintramuscular (or intradermal or subdermal) injection or implantation ofthe Clostridial neurotoxin.

6. the suppressant effects of the present methods can result in thedesirable side effects of greater patient mobility, a more positiveattitude, and an improved quality of life.

Although the present invention has been described in detail with regardto certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, a wide variety of neurotoxins can be effectively used inthe methods of the present invention. Additionally, the presentinvention includes local administration methods wherein two or moreClostridial neurotoxins, such as two or more botulinum toxins, areadministered concurrently or consecutively. For example, botulinum toxintype A can be locally administered until a loss of clinical response orneutralizing antibodies develop, followed by administration of botulinumtoxin type B. Furthermore, non-neurotoxin compounds can be locallyadministered prior to, concurrently with or subsequent to administrationof the neurotoxin to provide adjunct effect such as enhanced or a morerapid onset of suppression before the neurotoxin, such as a botulinumtoxin, begins to exert its more long lasting suppressant effect.

My invention also includes within its scope the use of a neurotoxin,such as a botulinum toxin, in the preparation of a medicament for thetreatment of an obsessive-compulsive disorder, by local administrationof the Clostridial neurotoxin.

All references, articles, patents, applications and publications setforth above are incorporated herein by reference in their entireties.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

1. A method of treating pruritis associated with psychosis in a patientwho suffers from auditory and visual hallucinations comprisingadministering a suitable quantity of botulinum toxin type A to alocation of skin itching to alleviate the pruritis associated withpsychosis in the patient, thereby treating the pruritis associated withpsychosis in the patient.
 2. The method of claim 1, wherein the quantityof the botulinum toxin type A administered is 4 units, 100 units, or2000 units.
 3. The method of claim 1, wherein the botulinum toxin type Ais administered subdermally at the location of the skin itching.
 4. Themethod of claim 2, wherein the administration of the botulinum toxintype A is to multiple sites of the skin itching.
 5. The method of claim4, wherein the skin itching is chronic.
 6. The method of claim 1,wherein one or more polymeric implants incorporating the botulinum toxintype A is placed at the location of the skin itching.
 7. The method ofclaim 1, wherein the alleviation persists from 1 to 5 years.
 8. Themethod of claim 1, wherein the alleviation persists for 4-6 months.